Aerobic exercise is widely recognized to reduce the risk of coronary heart disease, so much so that consensus panels routinely recommend physical activity as part of a cardioprotective regimen for healthy people. Surprisingly, the physiological or mechanistic basis of this protection is uncertain. One line of investigation has examined the possibility that this cardioprotection derives from the anti-inflammatory effects of exercise, because inflammation occupies a central role in the pathogenesis of atherosclerosis. This application aims to conduct a definitive study to determine whether aerobic exercise exerts a cardioprotective effect by suppressing production of inflammatory mediators and, secondarily, to examine if this suppression is via a mechanism of increasing vagus nerve activity. Understanding the mechanisms that underlie the beneficial effects of exercise is essential because it will allow development and testing of targeted interventions to produce comparable cardioprotective effects more directly or in cases where aerobic exercise is not possible. Moreover, it can lead to the therapeutic application of exercise in other diseases characterized by disorders of these underlying mechanisms. Thus, the potential significance of this application is substantial. A large body of evidence implicates inflammation in atherosclerosis but relatively few clinical studies of exercise and inflammation have been reported, and the conclusions from these studies are tempered by significant shortcomings in study design. Previous investigations generally have measured C-reactive protein (CRP) as the major endpoint. Although important, CRP, like acute-phase proteins, is at the downstream end of the inflammatory mediator cascade. Tumor necrosis factor (TNF), more upstream in this cascade, is rarely the focus of exercise studies despite evidence suggesting its role in plaque stability, endothelial dysfunction, and inflammatory damage in the arterial wall. Additionally, many studies are cross- sectional in nature. Studies employing training programs typically lack control groups or study only men. Our approach to this investigation addresses these shortcomings in several ways. We propose to conduct a randomized controlled trial of aerobic exercise vs. strength training to test the impact on cell production of TNF ex vivo, in the whole blood milieu. Study subjects will be young, healthy sedentary men and women, studied before and after 12 weeks of training and again after 4 weeks of sedentary deconditioning. Confirmation of our hypotheses will add considerably to the understanding of the benefits of physical exercise and is likely to have substantial clinical significance. PUBLIC HEALTH RELEVANCE: Aerobic exercise - the most widely recommended health behavior - is recognized to reduce the risk of coronary heart disease, so much so that consensus panels routinely include it as part of a cardioprotective regimen for healthy people, but the physiological or mechanistic basis of this protection is uncertain. Understanding the mechanisms has considerable public health significance because it will allow development and testing of targeted interventions to produce comparable cardioprotective effects more directly or in cases where aerobic exercise is not possible. This application proposes to test the hypothesis that aerobic training leads to attenuation of the inflammatory response to LPS stimulation and to examine the role played by exercise-induced increases in vagal activity, improvements in mood, and decreased expression of TLR4, the cognate receptor for endotoxin expressed by monocytes.